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  Delayed release pharmaceutical oral dosage form and method of making sameUSPTO Application #: 20070190139Title: Delayed release pharmaceutical oral dosage form and method of making same Abstract: The present invention relates to a multi layer pharmaceutical oral dosage form having delayed release and immediate release properties and method of making same. The delayed release formulation substantially behaves as an enterically coated dosage form but without the formulation and the application of an enteric coating. The delayed release formulation is characterized by a mixture of one or more active ingredients and one or more excipients selected from the group of solid aliphatic alcohols, mixtures of esters of saturated fatty alcohols and saturated fatty acids, natural or synthetic waxes, hydrogenated castor oil, hydrogenated vegetable oil, gums, and mixtures thereof; pH dependent soluble polymers; and optionally an opacifying agent. (end of abstract) Agent: Price Heneveld Cooper Dewitt & Litton, LLP - Grand Rapids, MI, US Inventors: Horst G. Zerbe, Pompilia Ispas-Szabo USPTO Applicaton #: 20070190139 - Class: 424468000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or Pills, Sustained Or Differential Release Type The Patent Description & Claims data below is from USPTO Patent Application 20070190139. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional Application No. 60/772,547 filed on Feb. 13, 2006 which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to a delayed release pharmaceutical oral dosage form and method of making same. More specifically, but not exclusively, the present invention relates to a delayed release pharmaceutical oral dosage form comprising a non-steroidal anti-inflammatory drug (NSAID), a prostaglandin analogue compound, and/or a proton pump inhibitor (PPI) and/or an H.sub.2-blocker. [0003] Methods for manufacture of the delayed release pharmaceutical oral dosage forms and use of the delayed release pharmaceutical oral dosage forms in treating disease are disclosed. BACKGROUND OF THE INVENTION [0004] Prostaglandin analogue compounds, such as the ones known under the generic names misoprostol, enoprostil, enisoprost and miraprostal, are orally active PGE.sub.1-analogs with mucosal protective and antisecretory properties. They are mainly used for preventing gastric and duodenal ulcers associated with NSAID treatment. They are commonly administered in separate, single unit dosage form, and sometimes in combination with an NSAID in a fixed dosage form. [0005] Proton pump inhibitors (PPIs) are a class of acid-labile pharmaceutical compounds that block gastric acid secretion pathways. Exemplary proton pump inhibitors include, omeprazole (Prilosec.RTM.), lansoprazole (Prevacid.RTM.), esomeprazole (Nexium.RTM.), rabeprazole (Aciphex.RTM.), pantoprazole (Protonix.RTM.), pariprazole, tenatoprazole, and leminoprazole. The drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H.sup.+/K.sup.+-ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to acid degradation and, as such, are rapidly destroyed in an acidic pH environment in the stomach. Therefore, proton pump inhibitors are often administered as enteric-coated dosage forms in order to permit release of the drug in the duodenum after having passed through the stomach. [0006] Histamine H.sub.2 receptor blocking agents (referred to herein as H.sub.2-blockers) are a class of drugs which act as antagonists of the histamine H.sub.2 receptor. H.sub.2 Blockers are effective means of inhibiting gastric acid secretion. Such compounds have a delayed onset, generally one to two hours after ingestion, and a long duration of action. Specific, H.sub.2 blockers include cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine and famotidine. [0007] Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used drugs world-wide. The ability of NSAIDs to treat inflammatory disorders is attributed to their ability to inhibit cyclooxygenase, the enzyme responsible for biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of lipoxygenase and cyclooxygenase (such as cyclooxygenase-I and cyclooxygenase-II). However, despite the therapeutic benefits of NSAIDs, their use is often limited by an increased risk of gastrointestinal side-effects, in particular upper gastrointestinal side-effects such as peptic ulceration, dyspeptic symptoms and risk of bleeding and perforation of the stomach (McGarty D. M., Gastroenterology 1989, 96, 662; Hawkey C, BMJ 1990, 300, 278). [0008] One promising solution to the problem of healing and preventing NSAID associated upper gastrointestinal problems, like ulcers and dyspeptic symptoms in patients needing continuous NSAID treatment, is to avoid contact between the NSAID and acidic gastric juice by delaying the NSAID release or to combine the NSAID treatment with an anti-ulcer drug approved for the healing and/or prophylaxis of NSAID associated gastrointestinal side-effects such as prostaglandin analogues, H.sub.2-blockers, and proton pump inhibitors. [0009] Pharmaceutical oral dosage forms are often better absorbed via the intestine. Delayed release pharmaceutical oral dosage forms can be obtained by applying an enteric film coating on a core tablet containing an active ingredient. Indeed, enteric film coatings have been widely used to allow pharmaceutical oral dosage forms to be released in the intestine rather than the stomach since many pharmaceutical products irritate the stomach due to their chemical properties. Moreover, other pharmaceutical products undergo chemical changes in gastric acid or by the action of stomach or saliva enzymes, thus becoming less effective. [0010] Enteric coatings are generally pH sensitive and will remain essentially impermeable at lower pH so as to pass through the stomach unscathed. Once in the higher pH region of the digestive tract, namely the intestinal tract, the coating will become permeable and allow the release of the active ingredient. Enteric coatings are commonly applied to a compressed tablet core or to individual beads or pellets which are then compressed into a tablet shape or placed in a reservoir capsule. Enteric coatings are widely sold under the trademarks Eudragit.RTM. by the Rohm Pharma and exist in various grades. [0011] The procedure of applying an enteric coating to a compressed tablet core generally consists in the preparation of aqueous dispersions/solutions or organic solutions including a polymer, plasticizers, glidants, anti-foam agents, fillers and pigments. The polymer is commonly selected from the class of cellulose derivatives or represents a polymer or copolymer of acrylic and/or methacrylic acid or esters thereof. In the case of the methacrylic polymer class, the coating is usually sprayed onto rotating tablets, pre-warmed to about 40.degree. C., and maintained at a temperature of approximately 40.degree. C. to 50.degree. C. during the entire process. A post-drying step, also known as tablet curing, contributes to film coalescence and improves the film coating characteristics. [0012] The use of enteric coatings, however, involves at least one additional process step, additional costs, and requires skill and know-how in the formulation and application of enteric coatings. Additional excipients such as plasticizers, glidants, anti-foaming agents, fillers and pigments are usually required to obtain suitable properties. For example, the coating must be of appropriate thickness, elasticity, porosity and/or stickiness. All of these parameters introduce additional technical and cost related factors into the manufacturing of enterically coated dosage forms. Various techniques commonly used for the application of enteric coatings include dry coating, spray coating and pan coating. [0013] The prior art on the subject of delayed release is often concerned with non-steroidal anti-inflammatory drug formulations. [0014] U.S. Pat. No. 5,698,225, issued to Gimet et al. on Dec. 16, 1997, proposes a combined NSAID and prostaglandin product. The product is enterically coated and is composed of a core comprising an NSAID selected from diclofenac and piroxicam, which core is surrounded by a mantle coating of a prostaglandin. An intermediate coating can optionally be present between the NSAID core and the prostaglandin mantle coating. [0015] U.S. Pat. No. 6,537,582, issued to Woolfe et al. on Mar. 25, 2003, proposes an oral pharmaceutical dosage form including a mixture of a delayed release formulation of an NSAID and a mixture containing a prostaglandin and one or more excipients. Methods describing the formation of coated granules are disclosed and comprise spraying a coating solution onto a bed of NSAID and any necessary excipients, for example, using a fluid bed coating apparatus. The process is controlled to produce fine granules which do not require milling before incorporation into tablets or capsules. The coating solution may include cellulose derivatives e.g. hydroxypropyl methyl cellulose, methacrylic acid and derivatives (e.g. methyl methacrylates), Eudragit.RTM., especially Eudragit L or S. Normally, the coating will include plasticizers, e.g. polyethylene glycol, triacetin or phthalate esters, conferring the required mechanical characteristics such as flexibility and hardness to the coating. [0016] U.S. Pat. No. 6,365,184, issued to Depui et al. on Apr. 2, 2002, and published U.S. Patent Application 2004/0022846A1 filed by Depui et al. and published on Feb. 5, 2004 describe an oral pharmaceutical dosage form comprising an acid susceptible proton pump inhibitor and one or more NSAIDs in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer. [0017] U.S. Pat. No. 6,287,600, issued to Ouali et al. on Sep. 11, 2001, discloses a stabilized pharmaceutical composition including an enterically coated NSAID, a prostaglandin and a prostaglandin stabilizing agent. In manufacturing the stabilized pharmaceutical composition, the NSAID was granulated by blending with suitable excipients (i.e. binders, fillers) in a fluid-bed granulator, followed by the application of an enteric coating. The enterically coated NSAID granules were then mixed with a prostaglandin comprising blend and tableted. [0018] As becomes readily apparent from the above, enterically coated systems involve additional process steps and the consideration of additional technical parameters which are time-consuming and which increase manufacturing costs. Coating ingredient selection, dispersion preparations and various technical parameters (i.e. temperature range, droplet size, type and content of plasticizer, etc.) are time-consuming operations and often, for an efficient protection, application of many layers (i.e. undercoatings) is necessary. Enteric coating performance, brittleness and stickiness underline critical shortcomings of enterically coated systems. [0019] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation." For example, solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated. [0020] Melt granulation techniques have also been developed in the art and constitute cost efficient, yet, for reasons further described below, seldomly applied processing techniques in the array of pharmaceutical manufacturing operations, including the manufacture of a variety of dosage forms and formulations such as immediate release and sustained release pellets, granules and tablets. Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation can then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution. However, melt granulation often requires high energy input and cannot be applied to heat-sensitive materials owing to the elevated temperatures involved. Moreover, the use of higher-melting-point binders requires higher melting temperatures which can contribute to instability problems, especially for heat-labile materials. On the up-side, melt granulation provides for a uniform dispersion of the active, involves fewer processing steps, (time consuming drying steps being eliminated), and provides for good stability at varying pH and moisture levels. [0021] U.S. Pat. No. 5,169,645, issued to Shukla et al. on Dec. 8, 1992, discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt. In either case, the melt combination of the wax(es) with the additive(s) yields, upon cooling and granulation, a wax-containing particulate drug diluent having improved and unexpected flow properties. [0022] A great many of the current pharmaceutical products suffer from light induced degradation of active ingredient(s). The traditional approach to remedy this problem has been to provide outer coatings on solid dosage forms, these protective coatings containing opacifying pigments such as titanium dioxide white. Moreover, these coatings commonly comprise polymers and additives to facilitate application and to provide good mechanical resistance. It is also known to mix pigments with active and inactive powder excipients. Continue reading... Full patent description for Delayed release pharmaceutical oral dosage form and method of making same Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Delayed release pharmaceutical oral dosage form and method of making same patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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